Abstract Fibrosing diseases such as pulmonary fibrosis are associated with up to 45% of the deaths in the US. In these diseases, inappropriate scar tissue called fibrotic lesions forms in internal organs. There are no FDA- approved therapies that reverse fibrosis, and much remains to be known about mechanisms driving fibrosis. In fibrotic lesions in mouse and human lungs, there is an increase in the levels of sialidases, enzymes that remove sialic acids from the distal tips of extracellular glycoproteins and other glycoconjugates. Sialidases appear to potentiate fibrosis at least in part by increasing levels of the pro-fibrotic cytokine TGF-?1 produced by some immune system cells. Conversely, TGF-?1 causes lung epithelial cells, lung fibroblasts, and some immune system cells to upregulate sialidases. Our hypothesis is that fibrosis is driven in part by a runaway positive feedback loop where sialidase potentiates fibrosis and fibrosis potentiates sialidase. In support of this hypothesis, we found that injections of two different sialidase inhibitors reduce pulmonary fibrosis in the mouse bleomycin model. To gain insight into what appears to be a fundamental mechanism linking the immune system to lung epithelial cells and fibroblasts, as well as a mechanism that helps drive fibrosis, we propose three specific aims. Since identifying the key sialidase(s) that is/are upregulated in fibrosis will identify potential targets to inhibit fibrosis, our first aim is to test the hypothesis that a sialidase called NEU3 is the major sialidase that potentiates fibrosis. Our second aim is to determine which immune system cells respond to sialidases and elucidate the receptor(s) whereby immune system cells sense the upregulated sialidases, and thus identify potential targets to block the feedback loop. Our third aim is to determine how sialidases cause an upregulation of TGF-?1, thus essentially working backwards on the sialidase sensing pathway toward the Aim 2 work. Together, this work will help to elucidate a novel mechanism that regulates the innate immune system and fibrosis, and may lead to new therapies for fibrosing diseases.